HIV/AIDS continues to cause enormous morbidity and mortality. Developing a vaccine that induces broadly reactive, neutralizing anti-HIV antibody is critically important, but so far no vaccine has been effective. A few such antibodies have been isolated from individual B cells of patients proving that they can be generated. Several of these antibodies have been shown to be polyspecific;they react with multiple antigens in addition to HIV, and they resemble antibodies formed in a part of the spleen termed the marginal zone (MZ). Cells of the MZ are first responders and act to destroy an initial inoculum of virus or bacteria before there is time to make a specific immune response. MZ B cells can also be stimulated to migrate to B cell follicles within the spleen, carrying their antigen. In the follicle, a more specific, high affinity antibody, like most of the antibody formed in AIDS patients, is generated. We focus on the known ability of HIV-1 and all retroviruses to mediate surface binding of proteins of the classical complement pathway, even in the absence of antibody, without being killed. There are three pathways of complement activation. Two of these prove critical. Most viruses and bacteria bind proteins of the alternative complement pathway. These proteins are designed to target and help destroy an initial inoculum of microbes, even before specific antibodies are formed. Most organisms do not bind proteins of the classical pathway. We have made the novel observation that the classical and alternative complement pathways direct antigens to entirely different sets of cellular receptors and can mediate different in vivo consequences. The binding of classical pathway proteins, but surprisingly not alternative pathway proteins, directs antigens to CD21, the C3d receptor, on MZ cells. We suggest that HIV uses this complement activating mechanism to mediate a critical stage in its life cycle. The classical complement proteins act as cofactors in triggering the transfer of MZ B-cells to the germinal center of the follicles where they are positioned for efficient transfer of virus to CD4 T cells. They also initiate a highly specific, but not broadly neutralizing, antibody response. The efficient transfer of MZ cells prevents the essential MZ polyspecific antibody response, required for initial protection. Antibody in antigen/antibody complexes is known to act as an adjuvant in immunization. We hypothesize that by using HIV antigen/antibody complexes prepared with antibodies that only activate the alternative complement pathway as a vaccine, the cycle will be interrupted. An appropriate broadly neutralizing, broadly specific antibody response will be generated by cells of the MZ, thus protecting patients from HIV infection. PUBLIC HEALTH RELEVANCE: The development of an effective, broadly neutralizing anti-HIV vaccine is a national priority. Thus far no vaccine has effectively prevented HIV infection. We propose a new strategy for the generation of an effective HIV vaccine, based on a new understanding of the role of complement in the life cycle of the organism.